Novel crystalline forms of gatifloxacin

ABSTRACT

Provided are novel crystalline forms of gatifloxacin denominated forms A, B, C, D, E1, F, G, H, I, and J, and methods for their preparation. Also provided are methods for making known crystalline forms of gatifloxacin, in particular forms omega and T2RP.

RELATED APPLICATIONS

The present application claims the benefit of the filing date of thefollowing U.S. Provisional Patent Applications: 60/379,510; 60/389,093;60/401,672; 60/402,749; 60/409,860, 60/423,338; 60/432,961; 60/444,812;and 60/448,062.

FIELD OF THE INVENTION

The present invent relates to novel polymorphs and pseudopolymorphs of(±)1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid, commonly known as gatifloxacin.

BACKGROUND OF THE INVENTION

Gatifloxacin, known as (±)1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid, has the following structure:

Gatifloxacin, an anti-bacterial agent, is marketed as Tequin® byBristol-Myers Squibb. Tequin® is available in a dosage of 200 and 400 mgin the form of a vial or a tablet, which can be either injected or takenorally.

Many pharmaceutically active organic compounds can crystallize in morethan one type of molecular packing with more than one type of internalcrystal lattice. That is, the compounds crystallize in differentcrystalline forms. The respective resulting crystal structures (forms)can have, for example, different unit cells. This phenomenon—identicalchemical structure but different internal structure—is referred to aspolymorphism and the species having different molecular structures arereferred to as polymorphs.

Many pharmacologically active organic compounds can also crystallize incrystalline forms such that second, foreign molecules, especiallysolvent molecules, are regularly incorporated into the crystal structureof the principal pharmacologically active compound. This phenomenon issometimes referred to as pseudopolymorphism and the resulting structuresas pseudopolymorphs. When the second molecule is a solvent molecule, thepseudopolymorphs can be referred to as solvates.

However, it is generally not possible to predict whether a particularorganic compound will form different crystalline forms, let alonepredict the structure and properties of the crystalline formsthemselves.

The discovery of a new crystalline form of a pharmaceutically usefulcompound provides an opportunity to improve the performancecharacteristics of a pharmaceutical product. It enlarges the repertoireof materials that a formulation scientist has available for designing,for example, a pharmaceutical dosage form of a drug with a targetedrelease profile or other desired characteristic. It is clearlyadvantageous when this repertoire is enlarged by the discovery of newpolymorphs or pseudopolymorphs of a useful compound. For a generalreview of polymorphs and the pharmaceutical applications of polymorphssee G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W.McCrone, J. Pharm. Sci., 58, 911 (1969); and J. K. Haleblian, J Pharm.Sci., 64, 1269 (1975), all of which are incorporated herein byreference.

Crystalline forms can be influenced by controlling the conditions underwhich the compound is obtained in solid form. Solid state physicalproperties that can differ from one polymorph to the next include, forexample, the flowability of the milled solid. Various crystalline formscan be more or less hygroscopic. Absorption of atmospheric moisture bycompound in powder form can impede its ability to flow. Flowabilityaffects the ease with which the material is handled during processinginto a pharmaceutical product. When particles of the powdered compounddo not flow past each other easily, a formulation specialist must takethat fact into account in developing a tablet or capsule formulation,which may necessitate the use of glidants such as colloidal silicondioxide, talc, starch or tribasic calcium phosphate.

Another important solid state property of a pharmaceutical compound thatcan vary from one polymorph or pseudopolymorph to the next is its rateof dissolution in aqueous media, e.g., gastric fluid. The rate ofdissolution of an active ingredient in a patient's stomach fluid canhave therapeutic consequences since it imposes an upper limit on therate at which an orally-administered active ingredient can reach thepatient's bloodstream. The rate of dissolution is also a considerationin formulating syrups, elixirs and other liquid medicaments. The solidstate form of a compound may also affect its behavior on compaction andits storage stability.

These practical physical characteristics are influenced by theconformation, orientation, and packing of molecules in the unit cell,which characterize a particular polymorphic or pseudopolymorphic form ofa substance. A polymorphic form may have thermodynamic propertiesdifferent from those of the amorphous material or another polymorphicform. Thermodynamic properties can be used to distinguish betweenvarious polymorphs or pseudopolymorphs. Thermodynamic properties thatcan be used to distinguish between polymorphs and pseudopolymorphs canbe measured in the laboratory by such techniques as capillary meltingpoint, thermogravimetric analysis (TGA), differential scanningcalorimetry (DSC), and differential thermal analysis (DTA).

A particular crystalline form can also possess distinct spectroscopicproperties that may be detectable by, for example, solid state ¹³C NMRspectroscopy and infrared (IR) spectroscopy. This is particularly so inthe case of crystalline forms that are solvates because of the presenceof absorptions or resonances due to the second, foreign molecule.

(±)-1-Cyclopropyl-6-fluoro-1,4-digydro-8-methoxy-7-(3-methyl-1-piperazinyl)4-oxo-3-quinolenecarboxylicacid, commonly known as gatifloxacin, is a synthetic broad-spectrumantibacterial agent for oral or intravenous administration.

U.S. Pat. No. 5,880,283 discloses that gatifloxacin forms a hygroscopichemihydrate. The hemihydrate (a pseudopolymorph) is reported to beeasily formed upon crystallization of gatifloxacin from water-containingorganic solvents. The hemihydrate reportedly has disadvantages formanufacturing of solid oral dosage forms, e.g., tablets. The patentfurther discloses a novel pseudopolymorph of gatifloxacin, thesesquihydrate, and presents thermal analysis and x-ray diffraction datafor this material. The sesquihydrate is reported to be less hygroscopicand more stable in manufacturing.

U.S. Pat. No. 6,413,969 discloses at least 12 different polymorphs orpseudopolymorphs of gatifloxacin and discloses the x-ray powderdiffraction diagrams of at least 10 of these. The hexahydrate,pentahydrate and sesquihydrate are crystallized directly from aqueoussolvents. Other crystalline forms are crystallized from a molten phaseor by solid-solid phase transformations. The pentahydrate form is,according to the disclosure of U.S. Pat. No. 6,413,969, the mostthermodynamically stable form and has the lowest aqueous solubility atroom temperature. The interrelationships between the twelve identifiedcrystalline forms are given in the application.

SUMMARY OF THE INVENTION

In one aspect, the present invention the present invention relates tocrystalline form of gatifloxacin, denominated form A, characterized byx-ray reflections at about 6.4°, 12.8°, 16.4°, 17.3°, and 19.4°±0.2° 2θ.

In another aspect the present invention relates to a crystalline form ofgatifloxacin, denominated form B, characterized by x-ray reflections atabout 9.2°, 10.6°, 11.9°, 18.4°, and 25.0°±0.2+ 2θ; and to a method formaking it, which method includes the steps of slurrying gatifloxacin ina lower alkanol selected from ethanol and 1-butanol at ambienttemperature for a slurry time, especially about 8 to about 36 hours, andisolating crystalline form B of gatifloxacin from the slurry.

In another aspect, the present invention relates to crystalline form ofgatifloxacin, denominated form C, having at least one characteristicselected from:

-   -   a) x-ray reflections at about 7.2°, 10.8°, 15.8°, 21.8°, and        26.2°±0.2°2θ,    -   b) DSC endotherms at about 173° and 177° C., and    -   c) FTIR absorption bands at about 805, 1509, 1619, and 1728        cm⁻¹.

In a related aspect, the present invention relates to a method of makinggatifloxacin form C including the step of heating either of gatifloxacinform B or form I at about 40° to about 70° C., especially 50° C., andatmospheric pressure for about 25 to about 48 hours.

In yet another aspect, the present invention relates to a crystallineform of gatifloxacin, denominated form D, characterized by x-rayreflections at about 8.2°, 14.4°, 19.0°, 21.4°, 21.9°, and 23.1°±0.2°2θ,and to a method of making it, which method includes the steps ofslurrying gatifloxacin in methanol at ambient temperature for a slurrytime, especially about 8 to about 36 hours, and isolating thecrystalline form of gatifloxacin from the slurry.

In another aspect, the present invention relates to a method of makingform D including the step of incubating gatifloxacin in vapors ofmethanol.

In a further aspect, the present invention relates to a crystalline formof gatifloxacin, denominated form F, characterized by x-ray reflectionsat 8.0°, 14.2°, 18.7°, 21.8°, and 23.0°±0.2° 2θ; and to a method ofmaking it, which method includes the steps of

a) providing a solution of gatifloxacin in a mixture of methanol andwater, 90:10 (v:v),

b) cooling the solution, especially to ambient temperature or below,especially about 5° C., and

c) isolating the crystalline form of gatifloxacin.

In another aspect, the present invention relates to crystalline form ofgatifloxacin, denominated form G, characterized by at least one of:

a) x-ray reflections at about 17.2° and 17.6°±0.2° 2θ, and

b) FTIR absorption bands at about 1614 cm⁻¹ and about 1267 cm⁻¹.

In a further aspect, the present invention relates to a method of makinggatifloxacin crystalline form G including the step of drying either ofgatifloxacin crystalline forms A or F at 50° C. and atmospheric pressurefor at least about 20 hours.

In yet another aspect, the present invention relates to a crystallineform of gatifloxacin, denominated form H, characterized by x-rayreflections at about 6.6°, 13.2°, 19.6°, and 19.9°±0.2°2θ; and to amethod of making it, which method includes the steps of:

a) providing a solution of gatifloxacin in toluene, especially at reflux

b) cooling the solution, especially to ambient temperature or below,especially about −5° C., and

c) isolating the crystalline form of gatifloxacin.

In another aspect, the present invention relates to gatifloxacin toluenesolvate.

In another aspect, the present invention relates to a method of makinggatifloxacin crystalline form H including the steps of:

a) slurrying gatifloxacin in toulene at ambient temperature for a slurrytime, especially about 8 to about 36 hours, and

b) isolating the crystalline form of gatifloxacin from the slurry.

In a further aspect, the present invention relates to a crystalline formof gatifloxacin, denominated form I, characterized by x-ray reflectionsat 6.5°, 7.1°, 12.8°, 17.2°, 19.3°, and 21.0°±0.2°, and to a method ofmaking it, which method includes the steps of:

a) providing a solution of gatifloxacin in 1-butanol, especially atreflux

b) cooling the solution, especially to ambient temperature or below,especially about −5°, and

c) isolating the crystalline form of gatifloxacin from the suspension.

In still yet another aspect, the present invention relates to acrystalline form of gatifloxacin that exists in various solvated forms,denominated form J, characterized by a x-ray reflection at about 6.7°,11.3°, 13.8°, and 16.4°±0.2° 2θ. Form J can exist at least as aniso-propanol solvate, that can be made by an incubation process or acrystallization process; a methyl ethyl ketone solvate that can be madeby an incubation process; an acetone solvate that can be made by anincubation process or slurry process; a 1-butanol solvate that can bemade by a crystallization process; or as a tetrahydrofuran solvate thatcan be made by a slurry process.

In still yet another aspect, the present invention relates to acrystalline form of gatifloxacin, denominated form E1, characterized byx-ray reflections at about 7.1°, 7.3°, 10.8°, 15.7°, 16.4°, and18.1°±0.2° 2θ; and to methods for making it. Form E1 containsacetonitrile, water, or a mixture of acetonitrile and water at up toabout 10 wt %.

In another aspect, the present invention relates to a crystalline formof gatifloxacin, E1-ACN, and to methods of making it. E1-ACN has thecrystallographic characteristics of E1, namely x-ray reflections atabout 7.1°, 7.3°, 10.8°, 15.7°, 16.4°, and 18.1°±0.2° 2θ; and containsup to about 10% acetonitrile.

Gatifloxacin E1-ACN can be made by a process including the steps of:

a) providing a solution of gatifloxacin in acetonitrile having about 5wt % or less water, especially about 4.5 wt % or less water, at reflux,

b) cooling the solution to a seeding temperature of about 57° to 70° C.,especially about 60° C.,

c) seeding the solution at the seeding temperature and, optionally,maintaining the seeded solution at the seeding temperature for a seedingtime of about 30 minutes or more,

d) cooling the seeded solution, especially to ambient temperature orbelow, especially 5° C. or below, and

e) isolating the crystalline E1-ACN gatifloxacin.

In still a further aspect, the present invention relates to a hydrateform E1 having a water content of about 7.5 to about 10 weight percent(wt %). In a particular aspect, the present invention relates to ahydrated form of gatifloxacin that is a dihydrate (E1 dihydrate) havingabout 9.3 weight percent water. The hydrated E1 of the presentinvention, regardless of water content, is substantially free ofprior-art sesquihydrate and is characterized by x-ray reflections atabout 7.1°, 7.3°, 10.8°, 15.7°, 16.4°, and 18.1°±0.2° 2θ.

In a further aspect, the present invention relates to methods of makinghydrated E1, which method includes the step of treating gatifloxacinform E1-ACN solvate with a moist gas, especially moist gas of about 55%to about 75% relative humidity at a temperature from ambient temperatureto about 60° C., especially about 20° to 30° C.; although treating at50° C. can be advantageous.

In still a further-aspect, the present invention relates to a method ofmaking prior-art crystalline form of gatifloxacin, denominated formomega (Ω), including the steps of:

a) providing, at reflux, a filtered solution of gatifloxacin inacetonitrile, wherein the solution has a water content of about 5% orless, especially about 4.5 wt % or less,

b) cooling the solution to a seeding temperature of about 50° to about56° C.

c) seeding the solution with gatifloxacin at the seeding temperatureand, optionally, maintaining the seeded solution at the seedingtemperature for a seeding time of at least about 30 minutes,

d) cooling the seeded solution, especially to ambient temperature orbelow, especially about 5° C., and

e) isolating the crystalline gatifloxacin crystalline form omega fromthe suspension.

In still a further aspect, the present invention relates to method ofmaking prior-art crystalline form of gatifloxacin T2RP. In one suchmethod, >200 g (especially >1000 g) of gatifloxacin E1-ACN are slurriedwith ethanol and the solid isolated from the slurry is treated withmoist gas, especially in a fluidized bed apparatus. Other methodsincluding the step of treating novel forms of gatifloxacin are alsodisclosed.

In another aspect, the present invention relates to a method of makingabout 200 g or less of gatifloxacin form T2RP including the steps ofslurrying about 200 g or less of gatifloxacin E1-ACN in ethanol,isolating the solid from the slurry, and drying the isolated solid atabout 50° C.

In another aspect, the present invention relates to gatifloxacin havingan average particle size less than about 100μ, especially less thanabout 50μ, wherein the gatifloxacin is in a crystalline form selectedfrom forms A, B, C, D, hydrated E1, F, G, H, I, and J.

In yet still another aspect, the present invention relates topharmaceutical compositions containing a hydrated form of gatifloxacinform E1, especially E1 dihydrate, that are substantially free ofsesquihydrate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a representative x-ray diffraction diagram of gatifloxacinform A.

FIG. 2 shows a representative DSC thermogram of gatifloxacin form A.

FIG. 3 shows a representative TGA thermogram of gatifloxacin form A.

FIG. 4 shows a representative x-ray diffraction diagram of gatifloxacinform B.

FIG. 5 shows a representative DSC thermogram of gatifloxacin form B.

FIG. 6 shows a representative TGA thermogram of gatifloxacin form B.

FIG. 7 shows a representative x-ray diffraction diagram of gatifloxacinform C.

FIG. 8 shows a representative FTIR spectra for gatifloxacin form C.

FIG. 9 shows a representative DSC thermogram of gatifloxacin form C.

FIG. 10 shows a representative TGA thermogram of gatifloxacin form C.

FIG. 11 shows a representative x-ray diffraction diagram of gatifloxacinform D.

FIG. 12 shows a representative DSC thermogram of form D.

FIG. 13 shows a representative TGA thermogram of form D.

FIG. 14 a through 14 g show representative x-ray diffraction diagrams ofgatifloxacin form E1.

FIG. 15 shows a representative TGA thermogram of gatifloxacin form E1dihydrate.

FIG. 16 shows a representative TGA thermogram of gatifloxacin form E1 asits acetonitrile solvate.

FIG. 17 shows a representative x-ray diffraction diagram of gatifloxacinform F.

FIG. 18 shows a representative DSC thermogram of form F.

FIG. 19 shows a representative TGA thermogram of form F.

FIG. 20 shows a representative x-ray diffraction diagram of gatifloxacinform G.

FIG. 21 shows a representative FTIR spectrum of gatifloxacin form G.

FIG. 22 shows a representative DSC thermogram of gatifloxacin form G.

FIG. 23 shows a representative TGA thermogram of gatifloxacin form G.

FIG. 24 shows a representative x-ray diffraction diagram of gatifloxacinform H toluene solvate.

FIG. 25 shows a representative DSC thermogram of gatifloxacin form Htoluene solvate.

FIG. 26 shows a representative TGA thermogram of gatifloxacin form Htoluene solvate.

FIG. 27 shows a representative x-ray diffraction diagram of gatifloxacinform I.

FIG. 28 shows a representative DSC thermogram of gatifloxacin form I.

FIG. 29 shows a representative TGA thermogram of gatifloxacin form I.

FIG. 30 shows a representative FTIR spectrum of gatifloxacin form J.

FIG. 31 shows a representative DSC thermogram of gatifloxacin form J.

FIG. 32 shows a representative TGA thermogram of gatifloxacin form J.

DETAILED DESCRIPTION OF THE INVENTION

Gatifloxacin, (±)1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid, is a known anti-bacterial. The present invention provides novelcrystalline forms (polymorphs, pseudopolymorphs) of this useful drug.

Unless otherwise specified or required by the context, gatifloxacinrefers to the compound in any crystalline form, which may or may not bea solvated crystalline form, or in an amorphous form.

As used herein, gatifloxacin form omega (Ω), form T1RP, and form T2RPrefer to the crystalline forms disclosed under those designations inU.S. Pat. No. 6,413,969. Gatifloxacin sesquihydrate refers to thecrystalline form of gatifloxacin denominated as such in U.S. Pat. No.5,880,283.

As used herein, the phrase, “having at least one characteristic of GTFform ‘#’,” where “#” is an arabic letter or numeral or a roman numeral,or any combinatiuon of these denoting a crystalline form ofgatifloxacin, refers to a crystalline form of gatifloxacin that exhibitsat least the characteristic powder x-ray diffraction (PXRD) reflections(or peaks), or the characteristic DSC endo- or exotherms, or, whereapplicable, the characteristic FTIR absorption bands of form ‘#’.

As used herein in connection with a measured quantity, the term,“about,” refers to that variation in the measured quantity as would beexpected by the skilled artisan making the measurement and exercising alevel of care commensurate with the objective of the measurement and theprecision of the measuring equipment used.

As used herein, the term ambient temperature is a temperature betweenabout 18° and about 30° C.

As used herein, ambient pressure is about 760 mmHg.

As used herein in connection with drying procedures, drying under vacuum(in vacuo) implies drying at a reduced pressure of about 10 to about 20mm Hg.

As used herein in connection with a multi-component mixture of liquids,the term % v/v refers to the ratio of the volume of the named componentto the sum of the volumes of all components used to make the mixture,times 100. Thus, a mixture of approximately equal volumes of A and B isreferred to as “50 vol-% A” (or 50 vol-% B). Alternatively, this mixturecan be referred to as “a mixture of A and B, 50:50 (v:v)”.

As used herein, lower alkanol refers to an alcohol of formulaC_(n)H_(2n+1)OH, where n is 6 or less.

X-ray reflections reported herein were determined by the powderdiffraction technique (PXRD). X-ray powder diffraction analysis wasperformed using a Scintag powder diffractometer with variablegoniometer, a Cu source, and a solid state detector. A standard roundaluminum sample holder with zero background quartz plate was used.Samples were scanned from 2° to 40° 2θ at 3° per minute. Reflections arereported as peak maxima in the Intensity vs. 2θ plots, and are subjectto the normal experimental error (uncertainty) of ±0.2°. Wet sampleswere promptly analyzed “as is,” i.e., without drying or grinding priorto the analysis.

Fourier transform infra-red spectra (FTIR) were obtained on Nujoll mullsusing a Perkin Elmer SpectrumOne spectrophotometer. Sixteen scans wererecorded from 4000 to 400 cm⁻¹ at a resolution of 4 cm⁻¹.

Differential scanning calorimetric (DSC) analysis was performed with aMettler Toledo DSC 821^(e) calorimeter. Samples of about 3 to about 5milligrams, held in a vented (3-hole) crucible, were analyzed at aheating rate of 10° per minute.

Thermogravimetric analysis (TGA) was performed using a Mettler TG50thermobalance. Samples of 7 to 15 milligrams were analyzed at a heatingrate of 10° C. per minute in the temperature range between about 25° C.and about 200° C.

The water content (wt-% water) of crystalline forms of gatifloxacinreported herein was determined by the Karl-Fisher method. Water contentof solutions was likewise determined by the Karl-Fisher method.

In particular embodiments, a novel crystalline form of the presentinvention is made by a crystallization (precipitation) process in whicha particular crystalline form of gatifloxacin is crystallized from asolution in an organic solvent. The solvent can be a single component(i.e., a single organic compound normally liquid at ambienttemperature), or it can be multi-component (i.e., a mixture of organiccompounds normally liquid at ambient temperature). One of the componentsof a multi-component solvent can be a poor solvent for gatifloxacin.Crystallization can be induced by changing the solubility ofgatifloxacin in the solvent. The solubility can be altered by, forexample, lowering the temperature of the solution, or by adding an“anti-solvent” to the solution.

In particular embodiments, filtration of the solution from which thecrystalline form of gatifloxacin is to be crystallized has been found tobe an important step. Although an understanding of the theory of theimportance of this filtration step is unnecessary to the practice of thepresent invention, the present inventors speculate that filtration,especially hot filtration, removes and promotes control of thetemperature at which nucleation can be sustained and crystallizationbegins. Both of these are parameters capable of influencing thecrystalline form of gatifloxacin obtained.

The temperature of the solution can be lowered in one or more steps. Formaking certain crystalline forms, it is advantageous to lower thetemperature in steps and-to maintain the temperature at each step for aholding time (i.e., a first holding time at the temperature at the endof the first cooling step, a second holding time at the temperature atthe end of the second cooling step, etc.). Step-wise lowering of thetemperature can be advantageous when seeding is employed. Seeding is awell-known technique for inducing crystallization of a compound from itssolution. When seeding is employed, the solution is cooled into aseeding temperature in a first cooling step. The temperature at whichthe solution is seeded is denoted the seeding temperature and theholding time at that temperature is known as a seeding time. It issometimes necessary to carefully control the cooling rate of any coolingstep, depending on the crystalline form of gatifloxacin being sought.

The skilled artisan will appreciate that in any method of the presentinvention in which a solution of gatifloxacin is provided, the solutioncan be provided by any means; for example by dissolving gatifloxacin inthe solvent or, where the solvent does not interfere with the reaction,by preparing gatifloxacin in the presence of the desired solvent, or inthe presence of one component of a multi-component solvent systemwhereafter other component(s) are introduced.

An anti-solvent is an organic compound, normally a liquid at ambienttemperature, that is a poor solvent for the compound to be crystallized(here gatifloxacin).

The solubility of the compound to be crystallized from the combinationof solvent and anti-solvent is lower than the solubility of the compoundin the original solvent. In particular embodiments, crystallization isinduced through use of an anti-solvent and by lowering the temperatureof the solution.

The crystalline form of gatifloxacin is then isolated by standard means.

In other embodiments, a novel crystalline form of gatifloxacin of thepresent invention is made in a slurry (suspension) process in whichgatifloxacin is slurried (suspended), with agitation, in a slurrysolvent, usually at ambient temperature, for a slurry time. As long asthere is sufficient slurry solvent to wet and suspend the gatifloxacin,the ratio of gatifloxacin to slurry solvent is not critical and will bedictated by practical considerations, for example, ease of handling. Theslurry time is not critical and will usually be between about 8 andabout 36 hours. The skilled artisan will know to adjust the slurry timeby routine optimization by, for example, isolating the solid from asmall aliquot of the slurry and determining the crystalline form of thesolid by an appropriate technique, for example x-ray diffraction,differential scanning calorimetry, or Fourier transform infra-redspectroscopy.

At the end of the slurry time, the crystalline form of gatifloxacin isisolated by standard techniques, for example filtration (gravity orsuction) or centrifugation, to mention just two.

In other embodiments, a novel crystalline form of gatifloxacin of thepresent invention is made by treating a vapor incubation process whereingatifloxacin is exposed to (i.e., incubated with) vapors of an organicsolvent, usually at ambient temperature, for an incubation time. Anysuitable chamber capable of holding the sample and containing thesolvent vapors can be used. The incubation time is not critical and willgenerally be between about 2 and about 20 days.

In those embodiments that yield a crystalline form of gatifloxacin thatis a solvate, care should be taken to analyze the material withoutdrying that might remove the solvent.

One or more of the foregoing methods, and other methods such as thermaltreatment (heating, drying) described hereinbelow, are adapted to thepreparation of the novel crystalline forms of gatifloxacin of thepresent invention.

In one embodiment, the present invention provide a crystalline form ofgatifloxacin, denominated form A, which is characterized by x-rayreflections at about 6.4°, 12.8°, 16.4°, 17.3°, and 19.4°±0.2° 2θ. Atypical x-ray diffraction diagram of form A is shown in FIG. 1. Atypical DSC thermogram of form A is shown in FIG. 2. The loss on dryingof form A, as determined by TGA, can be as high as 65%. A typical TGAthermogram of form A is shown in FIG. 3.

Form A can be made by a slurry process including the steps of slurryinggatifloxacin in iso-propanol (IPA) at ambient temperature and isolatingthe crystalline form A.

Form A can be converted to form J by, for example, drying at 50° C. Theskilled artisan will know to adjust the drying time according to, forexample, sample size and drying equipment used. Generally, a time ofabout 12 to about 18 hours is sufficient to effect the conversion.

In another embodiment, the present invention provides a novelcrystalline form of gatifloxacin, denominated form B, characterized byx-ray diffraction reflections at 2θ=9.2°, 10.6°, 11.9°, 18.4°, and25.0°. A typical x-ray diffraction diagram for form B is shown in FIG.4. A typical DSC thermogram of form B is shown in FIG. 5. A typical TGAthermogram of form B is shown in FIG. 6.

Gatifloxacin crystalline form B can be made in a slurry processincluding the steps of slurrying gatifloxacin at ambient temperature ineither 1-butanol or ethanol and recovering the gatifloxacin form B.

In still another embodiment, the present invention provides a novelcrystalline form of gatifloxacin, denominated form C, that can becharacterized by one or more of

-   -   a) x-ray reflections at about 7.2°, 10.8°, 15.8°, 21.8°, and        26.2°±0.2°2θ,    -   b) DSC endotherms at about 173° and 177° C., and    -   c) FTIR absorption bands at about 805, 1509, 1619, and 1728        cm⁻¹.

A typical x-ray diffraction diagram of form C is shown in FIG. 7. Atypical FTIR spectrum for form C is shown in FIG. 8. A typical DSCthermogram of form C is shown in FIG. 9. A typical TGA thermogram ofform C is shown in FIG. 10.

Form C can be made by, for example, drying form B, described above, atambient pressure and about 60° C., or at about 50° C. and 10 to 20 mmHg. Form C can also be made by drying form I, described hereinbelow, atabout 50° to about 60° C.

In another embodiment, the present invention provides a novelcrystalline form of gatifloxacin, denominated form D, characterized byx-ray reflections at about 8.2°, 14.4°, 19.0°, 21.4°, 21.9°, and23.1°±0.2° 2θ. A typical x-ray diffraction diagram for form D-is shownin FIG. 11. A typical DSC thermogram of form D is shown in FIG. 12. FormD has a loss on drying of about 13 wt %. A typical TGA thermogram ofform D is shown in FIG. 13.

Form D can be made by either a slurry process or a vapor incubationprocess. The slurry process for making form D includes the steps ofslurrying gatifloxacin with methanol and isolating gatifloxacin form D.In the vapor incubation process, gatifloxacin is incubated in vapors ofmethanol.

In still a further embodiment, the present invention provides a novelcrystalline form of gatifloxacin, denominated form E1. Form E1 can becharacterized by x-ray reflections at about 7.1°, 7.3°, 10.8°, 15.7°,16.4°, and 18.1°±0.2° 2θ. Typical x-ray diffraction diagrams fordifferent batches of form E1 are shown in FIGS. 14 a through 14 g, whichsuggest that small changes in the x-ray pattern may be observed indifferent batches, especially in the range of 19° to 30° 2θ.

Form E1 contains up to about 10% acetonitrile, water, or mixturesthereof. Form E1-ACN containing 8% to 10% acetonitrile can be referredto as monosolvate. The crystallographic properties of E1 are essentiallyinsensitive to the presence of the solvent. The solvent can bedriven-off by heating.

In a particular embodiment, the present invention provides a crystallineform of gatifloxacin, denominated E1-ACN, that has the crystallographicproperties of E1 and contains up to about 10% acetonitrile. A typicalTGA thermogram of E1-ACN is shown in FIG. 16. Drying of E1-ACN at 70° to170° C. for at least about 30 minutes yields gatifloxacin form omega(Ω).

E1-ACN can be made by a crystallization process including the steps ofproviding, at reflux, a solution of gatifloxacin in acetonitrile,wherein the water content of the solution is about 5 wt % or less,preferably 4.5 wt % or less, cooling the solution to a seedingtemperature between about 57° to 70° C., preferably about 60° C, seedingthe solution with gatifloxacin, optionally maintaining the seededsolution at the seeding temperature for a seeding time of about 30minutes or more, cooling the seeded solution to a temperature at whichE1-ACN crystallizes, especially to ambient temperature or below,preferably about 5° C. or below, and isolating the gatifloxacin E1-ACN.Typically, E1-ACN is isolated from a suspension.

The water content of the solution prior to seeding should be about 5 wt% or less, preferably 4.5 wt % or less, as determined by Karl-Fisheranalysis. If necessary, the water content can be reduced bydistilling-off acetonitrile-water azeotrope (replenishing acetonitrileas required).

E1-ACN can also be made by a vapor incubation method in whichgatifloxacin is incubated with vapors of acetonitrile for about 5 toabout 20 days.

In another embodiment, the present invention provides a hydrate form ofgatifloxacin having the crystallographic properties of form E1. Thehydrated form can but preferably does not also contain acetonitrile,with the proviso that the total amount of water and acetonitrile isabout 10% or less. In a preferred embodiment, the hydrated form containsabout 7.5% to about 10% water and is a dihydrate. A typical TGAthermogram of form E1 dihydrate is shown in FIG. 15.

The crystallographic characteristics of hydrated form E1 are those ofE1-ACN. Hydrated form E1 has a water content (Karl-Fisher) between about5% and about 10%, preferably 7.5% to 10%. In a particular embodiment,the hydrated form of E1 is form E1 dihydrate and contains about 9%water.

Hydrated form E1 can be made in a treating process including the step oftreating E1-ACN with a moist gas, such as air,. nitrogen, or a noblegas. Preferably, the moisture content of the gas is such that the gashas a relative humidity between about 55% and 75%. The treating can beat any temperature from ambient up to about 60° C. Preferably, thetreating is at about 20° to 30° C., most preferably 25° C.

Treating E1-ACN solvate with a moist gas at higher temperature than 30°C. results in hydrated E1 that can contain 5% to 7% water. By treatingthe E1 product which contains 5% to 7% water with a moist gas (55% -75%relative humidity) at 20° to 30° C., preferably 25° C., hydrated E1(water content of 7.5% to 10%) is obtained. In preferred embodiments, E1dihydrate of 9.3% water content is obtained.

Any apparatus that allows for circulation or percolation of moist gasaround and between particles of the E1-ACN can be used. Fluidized bedapparatus, well known in the art, is particularly well suited for thetreating.

The skilled artisan will know to adjust, within the limits discussedabove, the time and temperature to achieve the desired water content. Ifthe water content of a particular treated batch is lower than desired(or the acetonitrile content higher than desired), the batch can simplybe treated further to achieve the desired levels of water andacetonitrile.

The hydrated E1, especially E1 dihydrate, obtained in this or any otherembodiment of the present invention is substantially free of prior-artsesquihydrate. By substantially free is meant that the dihydratecontains about 5% or less of sesquihydrate.

A suitable method to determine the presence of gatifloxacinsesquihydrate in gatifloxacin form E1 is x-ray powder diffraction.Determination of presence of sesquihydrate in form E1 is feasible in theregion 7° to 9° 2θ, where a peak of sesquihydrate appears at about 7.8°2θ.

Moreover, the dihydrate of the present invention is stable againsttransformation to the sesquihydrate when exposed at ambient temperatureto 60% relative humidity for one week. A sample is considered stable ifthe sesquihydrate content does not rise by an amount detectable by PXRD,described above, upon storage.

The E1 dihydrate of the present invention is stable againsttransformation to sesquihydrate when stored at 30° C. and 60% relativehumidity for 3 months.

In another embodiment, the present invention provides a novelcrystalline form of gatifloxacin, denominated form F, characterized byx-ray reflections at 8.0°, 14.2°, 18.7°, 21.8°, and 23.0°±0.2° 2θ. Atypical x-ray diffraction diagram of form F is shown in FIG. 17. Atypical DSC thermogram of form F is shown in FIG. 18. A typical TGAthermogram of form F is shown in FIG. 19.

Form F can be made by a crystallization method including the steps ofproviding a solution, about 25% solids, of gatifloxacin in a mixture ofmethanol and water, 90:10 (v:v); cooling the solution, especially toambient temperature or below; and isolating the crystalline form ofgatifloxacin from the suspension. Drying form F yields form G, describedherein below.

In still a further embodiment, the present invention provides a novelcrystalline form of gatifloxacin, denominated form G, characterized byat least one of:

-   -   a) x-ray reflections at about 17.2° and 17.6°±0.2° 2θ, or    -   b) FTIR absorption bands at about 1614 cm⁻¹ and about 1267 cm⁻¹.

A typical x-ray diffraction diagram of form G is shown in FIG. 20. Atypical FTIR spectrum of form G is shown in FIG. 21. A typical DSCthermogram of form G is shown in FIG. 22. A typical TGA thermogram ofform G is shown in FIG. 23.

Form G can be made by, for example, drying either of form A or form F atabout 50° C. and atmospheric pressure for at least about 20 hours.

In a further embodiment, the present invention provides a novelcrystalline form of gatifloxacin, denomonated form H. Form H ischaracterized by x-ray reflections at about 6.6°, 13.2°, 19.6°, and19.9°±0.2°2θ. A typical x-ray diffraction diagram of form H toluenesolvate is shown in FIG. 24. A typical DSC-thermogram of form H toluenesolvate is shown in FIG. 25. A typical TGA thermogram of form H toluenesolvate is shown in FIG. 26.

Form H can be made by a crystallization method including-the steps of:providing a solution of gatifloxacin in toluene, preferably at reflux;cooling the solution to a temperature at which form H crystallizes,especially to ambient temperature or below, preferably 5° C. or below,and isolating the crystalline form of gatifloxacin from the suspension.

Form H can also be prepared by a slurry method including the steps ofslurrying gatifloxacin in toluene at ambient temperature for a slurrytime and isolating the crystalline form of gatifloxacin from the slurry.Preferred slurry times are between about 8 and about 36 hours.

In a further embodiment, the present invention provides a novelcrystalline form of gatifloxacin, denominated form I and characterizedby x-ray reflections at 6.5°, 7.1°, 12.8°, 17.2°, 19.3°, and21.0°±0.2°2θ. A typical x-ray diffraction diagram of form I is shown inFIG. 27. A typical DSC thermogram of form I is shown in FIG. 28. Atypical TGA thermogram of form I is shown in FIG. 29.

Form I can be made by a crystallization method including the steps of:

a) providing a solution of gatifloxacin in 1-butanol,

b) cooling the solution to a temperature at which form I crystallizes,especially to ambient temperature or below to obtain a suspension, and

c) isolating the crystalline form of gatifloxacin from the suspension.

Form I converts to hereinbelow described form J upon drying.

In still another embodiment, the present invention provides a novelcrystalline form of gatifloxacin, denominated form J, that exists asmultiple solvates. Regardless of solvation, form J is characterized byx-ray reflections at about 6.7°, 11.3°, 13.8°, and 16.4°±0.2° 2θ. Atypical FTIR spectrum of form J is shown in FIG. 30. A typical DSCthermogram of form J is shown in FIG. 31. A typical TGA thermogram ofform J is shown in FIG. 32.

Form J as its iso-propanol solvate can be made by incubatinggatifloxacin in vapors of iso-propanol, or by a crystallization methodthat includes the steps of:

a) providing a solution of gatifloxacin in iso-propanol,

b) cooling the solution to a temperature at which form J crystallizes,especially ambient temperature or below, and

c) isolating the crystalline form of gatifloxacin.

Form J as its iso-propanol solvate can also be made by heatinggatifloxacin form A at about 40° to about 70° C., preferably about 50°C. and atmospheric pressure.

Form J as its methyl ethyl ketone solvate can be made by incubatinggatifloxacin in vapors of methyl ethyl ketone.

Form J as its acetone solvate can be made by a slurry process includingthe steps of slurrying gatifloxacin in acetone at ambient temperature,and isolating the crystalline acetone solvate form J gatifloxacin fromthe slurry.

Form J as its tetrahydrofuran solvate can be made by a slurry processincluding the steps of slurrying gatifloxacin in tetrahydrofuran atambient temperature, and isolating the crystalline form Jtetrahydrofuran solvate.

Form J as its 1-butanol solvate can be made by a crystallization methodincluding the steps of:

a) providing a solution of gatifloxacin in 1-butanol, preferably atreflux

b) cooling the solution to a temperature at which form J crystallizes,especially ambient temperature or below, especially about 5° C., and

c) isolating the crystalline gatifloxacin form J 1-butanol solvate.

Total loss-on-drying (LOD) values, step weight-losses, and watercontents for form J as several of its solvates are summarized in Table Ibelow. TABLE I LOD, KF and Corresponding Solvate Formulas of form JSamples Total Weight Weight loss Karl Corresponding Loss step (≈80-Fisher Solvate Solvent By TGA (%) 145° C.) (wt-%) Formula IPA 8.7 4.14.01 GTF:IPA (4:1) (Theoretical value: 3.8%) 1-BuOH 10.4 7.6 2.79GTF:n-BuOH (5:2) (Theoretical value: 7.3%) IPA 8.7 6.4 2.42 GTF:IPA(5:2) (Theoretical value: 6.0%) IPA 8.3 4.9 4.84 GTF:IPA (3:1)(Theoretical value: 5.0%) Acetone 8.9 4.3 3.45 GTF:Acetone (3:1)(Theoretical value: 4.9%) IPA 11.4 7.8 3.13 GTF:IPA (2:1) (Theoreticalvalue: 7.4%)

In still further embodiments, the present invention provides methods ofmaking the prior-art crystalline form of gatifloxacin denominated formomega (Ω).

In one such embodiment, the present invention provides a crystallizationmethod of making gatifloxacin form omega including the steps of:

a) providing a filtered solution of gatifloxacin in acetonitrile,wherein the solution has a water content of about 5% or less, preferablyabout 4.5 wt % or less, at a temperature of about 80° C. or higher,preferably

b) cooling the solution to a seeding temperature of about 50° to about56° C.

c) seeding the solution with gatifloxacin at the seeding temperatureand, optionally, maintaining the seeded solution at the seedingtemperature for a seeding time of about 30 minutes or more,

d) cooling the seeded solution to a temperature at which form omegacrystallizes, preferably to ambient temperature or below, mostpreferably about 5° C., and

e) isolating the gatifloxacin crystalline form omega.

As discussed in relation to for E1, the water content of thehot-filtered solution can be adjusted to the desired range by distillingoff water-acetonitrile azeotrope.

In another embodiment, the present invention provides a method of makinggatifloxacin form omega including the step of heating form J to about90° to about 170° C., preferably about 120° C., at atmospheric pressure.

In a further embodiment, the present invention provides a method ofmaking gatifloxacin form omega including the steps of heating form E1 atabout 70° to 170° C. for at least about 30 minutes.

In yet still a further embodiment, the present invention provides amethod of making gatifloxacin form omega including the steps of heatinggatifloxacin form G at about 120° C. In yet other embodiments, thepresent invention provides a method of making the prior art hemihydratecrystalline form of gatifloxacin, denominated T2RP, via the novelgatifloxacin E1. Thus in one embodiment, useful when the amounts ofgatifloxacin are about 200 g or less, the present invention provides amethod of making T2RP including the steps of slurrying gatifloxacin E1with ethanol, isolating the solid from the slurry, and drying the solidin vacuo to obtain gatifloxacin T2RP.

In a related embodiment, useful with >200 gram quantities ofgatifloxacin or more, the present invention provides a method of makinggatifloxacin form T2RP including the steps of slurrying kilogramquantities of gatifloxacin in ethanol isolating the solid from theslurry, and treating the isolated solid with moist air, as is done inmaking E1 dihydrate from E1-ACN.

In another embodiment, the present invention provides a method of makingform T2RP including the step of heating, at atmospheric pressure, theprior-art sesquihydrate at about 80° to about 150° C., preferably 120°C.

In another embodiment, the present invention provides a method of makinghemihydrate T2RP including the step of heating, at atmospheric pressure,novel gatifloxacin form G about 80° to about 130° C., preferably 120° C.to effect the conversion.

In still yet another embodiment, the present invention provides novelcrystalline gatifloxacin forms A, B, C, D, E1, F, G, H, I, and J havingan average particle size of 100 μm or less, preferably 50 μm or less.

The present invention provides a plurality of particles of any of thegatifloxacin forms A, B, C, D, E1, F, G, H, I, and J having the diameterof all particles in the plurality equal to or less than about 100 μm;preferably, equal to or less than about 50 μm. Particles of theplurality will vary in characteristics and the characteristics of noindividual or small proportion of the particles will materially affectthe advantages afforded by this invention which may include more rapiddissolution and the potential for improved bioavailability. Rather, thecharacteristics of the pharmaceutical composition are determined from astatistically significant sampling of the composition and measurement ofbulk, or average, properties of the sample. Statistically significantmeasurements include those with a statistical sampling error of about 2%or less. The “average particle diameter” refers to the equivalentspherical diameter as determined by well-known methods, e.g., laserlight scattering method, or sieving methods.

Gatifloxacin of the above-defined defined particle diameter may beproduced by known methods of particle size reduction starting withcrystals, powder aggregates and coarse powder of gatifloxacin of one ormore of crystalline forms A, B, C, D, E1, F, G, H, I, and J. Theprincipal operations of conventional size reduction are milling of afeedstock material and sorting of the milled material by size.

A fluid energy mill, or micronizer, is an especially preferred type ofmill for its ability to produce particles of small size in a narrow sizedistribution. As those skilled in the art are aware, micronizers use thekinetic energy of collision between particles suspended in a rapidlymoving fluid (typically air) stream to cleave the particles. Thesuspended particles are injected under pressure into a recirculatingparticle stream. Smaller particles are carried aloft inside the mill andswept into a vent connected to a dust collector. The feedstock may bepre-milled to about 150 to 850 μm.

Examples of a useful micronizers include a fluid energy mill such asMicrogrinding MC-300 KX, (Microgrinding Ltd., 6995 Molinazzo diMonteggio, CH), Alpine-Hosokawa Fluidized bed opposed jet mill, modelAFG (Alpine-Hosokawa, Peter Dorfler Strs., D-8900, DE) and Sturtaventmicronizer jet mill (Sturtavent, 348 Circuit St., Hanover, Mass., USA).Alternatively, a pinmill such as Alpine UPZ 160 or similar equipment canbe used.

The feed material to the micronizer can have an average PSD about100-200 microns. The material is fed into the micronization system in acontrolled feed rate by means of a screw feeder or a vibratory feeder.The air jet mill is operated with controlled air pressures. For theMicrogrinding MC-300 KX, the feed rate is 40-60 kg/hr, the feed airpressure is 6-8.5 bar and the grinding air is 3-6 bar.

The material is fed into the mill system in a controlled feed rate bymeans of a screw feeder or a vibratory feeder. The mill is operated withcontrolled speed. For the Alpine UPZ 160, the feed rate is 60-75 kg/hr,the mill speed is 7000-15,000 rpm.

The novel crystalline forms of the present invention, as a plurality ofparticles of particle size ≦100 μm, especially ≦50 μm, are particularlyuseful for the preparation of pharmaceutical compositions.

Thus, in still yet a further embodiment, any of the novel crystallineforms of gatifloxacin, forms A, B. C. D. E1. F.G, H, I, or J describedhereinabove, alone or in any combination, are formulated into apharmaceutical composition, preferably an oral solid dosage form or adosage form for parental administration. Preferably, the crystallineform of the gatifloxacin used in making the pharmaceutical compositionhas a maximum particle size of 100 μm or less, preferably 50 μm or less.

The pharmaceutical composition can be in the form of a solid oral dosageform (e.g., compressed tablets or capsules), or it can be in the form ofa liquid oral dosage form (e.g., a solution or oral suspension). It wasfound that E1 is also stable in formulations at 30° C. for at least 3months.

Compressed tablets can be made by dry or wet granulation methods as isknown in the art. In addition to the pharmaceutically active agent ordrug, compressed tablets contain a number of pharmacologically inertingredients, referred to as excipients. Some excipients allow orfacilitate the processing of the drug into tablet dosage forms. Otherexcipients contribute to proper delivery of the drug by, for example,facilitating disintegration.

Excipients can be broadly classified according to their intendedfunction. This classification is sometimes arbitrary and it is knownthat a particular excipient can function in more than one way or servemore than one purpose in a formulation.

Diluents increase the bulk of a solid pharmaceutical composition and maymake a pharmaceutical dosage form containing the composition easier forthe patient and caregiver to handle. Diluents for solid compositionsinclude, for example, microcrystalline cellulose (e.g., AVICEL®,microfine cellulose, lactose, starch, pregelatinized starch, calciumcarbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasiccalcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g., EUDRAGIT®), potassium chloride, powderedcellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage formlike a tablet may include excipients whose functions include helping tobind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g., carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.,KLUCEL®), hydroxypropyl methyl cellulose (e.g., METHOCEL®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g., KOLLIDON®, PLASDONE®), pregelatinizedstarch, sodium alginate and starch. The dissolution rate of a compactedsolid pharmaceutical composition in the patient's stomach may beincreased by the addition of a disintegrant to the composition.

Disintegrants include alginic acid, carboxymethylcellulose calcium,carboxymethylcellulose sodium (e.g., AC-DI-SOL®, PRIMELLOSE®), colloidalsilicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON®,POLYPLASDONE®), guar gum, magnesium aluminum silicate, methyl cellulose,microcrystalline cellulose, polacrilin potassium, powdered cellulose,pregelatinized starch, sodium alginate, sodium starch glycolate (e.g.,EXPLOTAB®) and starch.

Glidants can be added to improve the flow properties of non-compactedsolid compositions and improve the accuracy of dosing. Excipients thatmay function as glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, talc and tribasic calciumphosphate.

When a dosage form such as a tablet is made by compaction of a powderedcomposition, the composition is subjected to pressure from a punch anddie. Some excipients and active ingredients have a tendency to adhere tothe surfaces of the punch and die, which can cause the product to havepitting and other surface irregularities. A lubricant can be added tothe composition to reduce-adhesion and ease release of the product fromthe die. Lubricants include magnesium stearate, calcium stearate,glyceryl monostearate, glyceryl palmitostearate, hydrogenated castoroil, hydrogenated vegetable oil, mineral oil, polyethylene glycol,sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearicacid, talc and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that may be included in the composition ofthe present invention include maltol, vanillin, ethyl vanillin, menthol,citric acid, fumaric acid ethyl maltol, and tartaric acid.

Solid and liquid compositions may also be colored using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

Of course, wet or dry granulate can also be used to fill capsules, forexample gelatin capsules. The excipients chosen for granulation when acapsule is the intended dosage form may or may not be the same as thoseused when a compressed tablet dosage form is contemplated.

Selection of excipients and the amounts to use may be readily determinedby the formulation scientist based upon experience and consideration ofstandard procedures and reference works in the field.

In liquid pharmaceutical compositions of the present invention, one ofGTF forms A, B, C, D, E1, F, G, H, I, and J, or mixtures thereof, andany other solid excipients are dissolved or suspended in a liquidcarrier such as water, vegetable oil, alcohol, polyethylene glycol,propylene glycol or glycerin.

Liquid pharmaceutical compositions can contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that can be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention can alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include, for example, acacia, alginic acid, bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanthand xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol and invert sugar can be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxy toluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid can be added at levels safe for ingestion to improvestorage stability.

A liquid composition according to the present invention can also containa buffer such as gluconic acid, lactic acid, citric acid or acetic acid,sodium gluconate, sodium lactate, sodium citrate or sodium acetate.

The solid compositions of the present invention include powders,granulates, aggregates and compacted compositions. The dosages includedosages suitable for oral, buccal, rectal, parenteral (includingsubcutaneous, intramuscular, and intravenous), inhalant and ophthalmicadministration. The most suitable route in any given case will depend onthe nature and severity of the condition being treated. The dosages canbe conveniently presented in unit dosage form and prepared by any of themethods well-known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches and losenges as well as liquid syrups,suspensions and elixirs.

The active ingredient and excipients can be formulated into compositionsand dosage forms according to methods known in the art.

A composition for tableting or capsule filling can be prepared by wetgranulation. In wet granulation some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water, which causes the powders to clumpup into granules. The granulate is screened and/or milled, dried andthen screened and/or milled to the desired particle size. The granulatecan then be tableted or other excipients can be added prior totableting, such as a glidant and/or a lubricant.

A tableting composition can be prepared conventionally by dry blending.For instance, the blended composition of the active ingredients andexcipients can be compacted into a slug or a sheet and then comminutedinto compacted granules. The compacted granules can be compressedsubsequently into a tablet.

As an alternative to dry granulation, a blended composition can becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well-suited todirect compression tableting include microcrystalline cellulose, spraydried lactose, dicalcium phosphate dihydrate and colloidal silica. Theproper use of these and other excipients in direct compression tabletingis known to those in the art with experience and skill in particularformulation challenges of direct compression tableting.

A capsule filling of the present invention can comprise any of theaforementioned blends and granulates that were described with referenceto tableting, only they are not subjected to a final tableting step.

Capsules, tablets and lozenges and other unit dosage forms may beadministered in various dosages depending on the need.

The present invention can be further illustrated with the followingnon-limiting examples.

EXAMPLES Example 1 Form A

3 g of gatifloxacin were slurried in 20 mL of iso-propanol (IPA). Themixture was slurried at ambient temperature for a slurry time of 24hours with a magnetic stirrer. The mixture was filtered under vacuum,rinsed with iso-propanol (IPA) (10 mL) and analyzed by XRD analysis andshowed to be form A.

Example 2 Form B

3 g of gatifloxacin were slurried in 20 mL of 1-butanol. The mixture wasstirred at ambient temperature for a slurry time of 24 hours with amagnetic stirrer. Then the mixture was filtered under vacuum, theisolated solid rinsed with 1-butanol (10 mL), and analyzed by XRDanalysis.

A second portion of the solid obtained after filtration was dried undervacuum at 50° C. for 24 hours. This resulted in a partially amorphousform B.

Example 3 Form B

3 g of gatifloxacin were slurried in 20 mL of EtOH absolute. The mixturewas stirred at ambient temperature for a slurry time of 24 hours with amagnetic stirrer. Then the mixture was filtered under vacuum, theisolated solid rinsed with absolute EtOH (10 mL), and analyzed by XRD.The product was partially amorphous form B.

Example 4 Form C

3 g of gatifloxacin were slurried in 20 mL of 1-butanol. The mixture wasstirred at ambient temperature for a slurry time of 24 hours with amagnetic stirrer. The mixture was then filtered under vacuum, theisolated solid rinsed with 1-butanol (10 mL), and dried at atmosphericpressure in an oven at 60° C. for 24 hours.

Example 5 Form C

5 g of gatifloxacin were suspended in 40 mL of 1-butanol. The mixturewas heated to reflux temperature until complete dissolution of thematerial. The solution was then stirred at this temperature for 5minutes, cooled to ambient temperature, and then to 5° C. The stirringwas maintained at this temperature for one hour and then the mixture wasfiltered under vacuum. The solid obtained was put in an atmospheric ovenat 60° C. for 40 hours. The sample was analyzed by PXRD and found to beform C.

Example 6 Form D

3 g of gatifloxacin were slurried in 20 mL of methanol. The mixture wasstirred at ambient temperature for a slurry time 24 hours with amagnetic stirrer. Then the mixture was filtered under vacuum, theisolated solid rinsed with methanol (10 mL) and analyzed by XRD.

Example 7 Form D

2 g of gatifloxacin were put in a beaker. This beaker was put open in abottle-containing methanol. Then this bottle was hermetically closed for15 days in order to create an atmosphere saturated with methanol vapors.The sample was then analyzed by XRD analysis.

Example 8 Form F

5 g of gatifloxacin were put in suspension in 20 mL of a aqueoussolution of MeOH 90%. The mixture was heated to reflux temperature and asolution of MeOH 90% (109 mL) was added to complete the dissolution ofthe material. The solution was then stirred at this temperature for 5minutes, cooled to ambient temperature, and then to 5° C. The mixturewas maintained at this temperature for one hour and then was filteredunder vacuum. The sample was analyzed by PXRD, with no further drying,and found to be form F.

Example 9 Form G

5 g of gatifloxacin were put in suspension in 20 mL of a aqueoussolution of MeOH 90%. The mixture was heated to reflux temperature and asolution of MeOH 90% (109 mL) was added to complete the dissolution ofthe material. The solution was then stirred at this temperature for 5minutes, cooled to ambient temperature, and then to 5° C. The mixturewas maintained at this temperature for one hour and then was filteredunder vacuum. The sample was dried in an atmospheric oven at 60° C. for24 hours. These samples were analyzed by XRD analysis and found to beform G.

Example 10 Form H

3 g of gatifloxacin were slurried in 20 mL of toluene. The mixture wasstirred at ambient temperature for a slurry time of 24 hours with amagnetic stirrer. Then the mixture was filtered under vacuum, theisolated solid rinsed with toluene (10 mL). The sample was analyzed byPXRD analysis with no further drying.

Example 11 Form H

5 g of gatifloxacin were put in suspension in 50 mL of toluene equippedwith a condenser and a Dean-Stark trap. The mixture was heated to refluxuntil complete dissolution of the material. After 10 minutes of a strongreflux the solution was cooled to ambient temperature, and then to 5° C.The mixture was maintained at this temperature for one hour and then wasfiltered under vacuum. The sample was analyzed by XRD analysis with nofurther drying.

Example 12 Form I

5 g of gatifloxacin were put in suspension in 40 mL of 1-butanol. Themixture was heated to reflux temperature until complete dissolution ofthe material. The solution was then stirred at this temperature for 5minutes, cooled to ambient temperature, and then to 5° C. The stirringwas maintained at this temperature for one hour and then the mixture wasfiltered under vacuum. The sample was analyzed by XRD analysis with nofurther drying.

Example 13 Form J

3 g of gatifloxacin were slurried in 20 mL of technical IPA. The mixturewas stirred at ambient temperature for a slurry time of 24 hours with amagnetic stirrer. Then the mixture was filtered under vacuum and theisolated solid rinsed with technical IPA (10 mL). The sample was dividedin two portions. The first portion was dried in a vacuum oven at 50° C.for 24 hours and the second portion was dried in an atmospheric oven at60° C. for 24 hours. These two dried samples were analyzed by XRDanalysis and shown to be form J.

Example 14 Form J

2 g of gatifloxacin were put in a beaker. This beaker was put open in abottle-containing isopropanol. Then this bottle was hermetically closedfor 15 days in order to create an atmosphere saturated with isopropanolvapors. The sample was then analyzed by XRD analysis.

Example 15 Form J

2 g of gatifloxacin were put in a beaker. This beaker was put open in abottle-containing methylethyl ketone. Then this bottle was hermeticallyclosed for 15 days in order to create an atmosphere saturated withmethylethyl ketone vapors. The sample was then analyzed by XRD analysis.

Example 16 Form J

3 g of gatifloxacin were slurried in 20 mL of acetone. The mixture wasstirred at ambient temperature for a slurry time of 24 hours with amagnetic stirrer. Then the mixture was filtered under vacuum, and theisolated solid rinsed with acetone (10 mL). The sample was divided intwo portions. The first portion was not dried and the second portion wasdried in a vacuum oven at 50° C. for 24 hours. These two samples wereanalyzed by XRD analysis and found to be form J.

Example 17 Form J

3 g of gatifloxacin were slurried in 20 mL of THF. The mixture wasstirred at ambient temperature for a slurry time of 24 hours with amagnetic stirrer. Then the mixture was filtered under vacuum, rinsedwith THF (10 mL). The sample was divided in two portions. The firstportion was not dried and the second portion was dried in a vacuum ovenat 50° C. for 24 hours. These two samples were analyzed by XRD analysisand found to be form J.

Example 18 Form J

5 g of gatifloxacin were put in suspension in 30 mL of technical IPA.The mixture was heated to reflux temperature and IPA (39 mL) was addedto get the complete dissolution of the material. The solution was thenstirred at this temperature for 5 minutes, cooled to ambienttemperature, and then to 5° C. The stirring was maintained at thistemperature for one hour and then the mixture was filtered under vacuum.The solid was divided in three portions. The first portion was notdried, the second portion was dried in a vacuum oven at 50° C. for 24hours and the third portion was dried in an atmospheric oven at 60° C.for 24 hours. These three samples were analyzed by XRD analysis andfound to be form J.

Example 19 Form J

5 g of gatifloxacin were put in suspension in 40 mL of 1-butanol. Themixture was heated to reflux temperature until complete dissolution ofthe material. The solution was then stirred at this temperature for 5minutes, cooled to ambient temperature, and then to 5° C. The stirringwas maintained at this temperature for one hour and then the mixture wasfiltered under vacuum. The sample was dried in a vacuum oven at 50° C.for 24 hours and analyzed by XRD analysis and found to be form J.

Example 20 Form E1-ACN

Gatifloxacin (20 g) was charged to a 150 mL reactor equipped with amechanical stirrer and thermometer. Acetonitrile (140 mL) was added andthe mixture was heated to 85° C. until a clear solution formed. Hyflow®(5%) was added to the solution and the solution was stirred at 85° C.for 1 hour. A hot filtration was then performed through a jacketedBuchner funnel at 80° C. and the solution was transferred in a cleanreactor at 85° C. The solution was then maintained at 85° C. for 5minutes, then cooled to 60° C. over 30 minutes. At this temperature(seeding temperature) the solution was seeded with gatifloxacin solid,maintained for 1 hour at 60° C. (i.e., seeding time=1 hour), and thencooled to 5° C. over 5 hours. The resulting suspension was thenmaintained at 5° C. for 1 hour. The mixture was filtered under vacuum.The isolated solid was washed with acetonitrile (15 mL) and dried in avacuum oven at 50° C. overnight.

The dry sample was analyzed by XRD and found have the characteristic XRDreflections of form E1.

Example 21 Hydrated E1

A 1 liter reactor equipped with mechanical stirrer, condenser andthermometer, was charged with gatifloxacin (crude dry; 100 g) andacetonitrile (ACN 1000 mL). The slurry was then heated to reflux (80°C.) and stirred at a rate of 400 rpm. The heating was continued for 0.5hours until clear solution was obtained.

The clear solution was cooled to 56-58° C. and seeded with 0.1 g of GTF.At the end of the addition the seeded solution was maintained for aseeding time of 2 hours at the seeding temperature of 56-58° C., thencooled over 8 hours to a temperature of 5° C. The temperature wasmaintained at 5° C., with stirring for 12 hours.

The resulting slurry was filtered (suction) and the collected solidwashed with ACN (150 mL) to obtain 91.7 g of wet material.

The wet sample was analyzed by XRD and found to be E1 (Water content byKF=2.48 wt %).

The material obtained was loaded into a Fluidized bed drier and treatedat 50° C. for 4 hours with to obtain 84 g of gatifloxacin crystals, formE1 dihydrate.

The sample was analyzed by XRD and found to be E1 (Water content byKF=8.25 wt %).

Example 22 E1-ACN

2 g of gatifloxacin were put in a beaker. This beaker was put open in abottle-containing acetonitrile. Then this bottle was hermetically closedfor 15 days in order to create an atmosphere saturated with acetonitrilevapors. The sample was then analyzed by XRD analysis.

Example 23 Form Ω

Gatifloxacin (crude, 15 g) was charged to a 250 mL reactor equipped witha mechanical stirrer and thermometer. Acetonitrile (110 mL) was addedand the mixture was heated to 85° C. until a clear solution formed.Hyflow® (5%) was added to the solution was stirred at 85° C. for 30minutes. A hot filtration was then performed through a jacketed Buchnerfunnel at 80° C. and the solution was charged to a reactor at 85° C. Thesolution was maintained at 85° C. for 1 h30, then cooled to 55° C. over1 hour. At 55° C. the solution was seeded with gatifloxacin solid andmaintained for 30 minutes at 55° C. The resulting suspension was thencooled to 50° C. over 30 minutes, maintained at this temperature for 30minutes, cooled to 5° C. over 2 hours, and maintained at 5° C. for 1hour. The mixture was filtered under vacuum and dried in a vacuum ovenat 50° C. overnight.

The dry sample was analyzed by XRD and found to be form Ω.

Example 24 T2RP

Form E1 (1 g) was slurried in 6.6 mL of ethanol and stirred at ambienttemperature for 2 hours. The slurry was then filtered under vacuum andthe collected solid washed with ethanol (3 ml). The washed collectedsolid was then dried at 50° C. overnight and was analyzed by XRDanalysis and shown to be form T2RP.

Example 25 T2RP

3 g of dry form Ω were put in a flask equipped with a condenser and amagnetic stirrer. Ethanol (19.8 mL) was added and the slurry was stirredat ambient temperature for 4 hours. A portion of the solid isolated fromthe slurry was dried at 50° C. under vacuum until constant weight andthen was analyzed by XRD. This sample was form T2RP.

Example 26 Form T2RP Hemihydrate

A 10 liter reactor equipped with mechanical stirrer, condenser andthermometer, was charged with GTF-Crude dry (1 Kg) and acetonitrile (10liter). The slurry was then heated to reflux (80° C.) and stirred at arate of 400 rpm for 2 hours at this temperature to obtain a solution.The solution was filtered. The clear solution was cooled to 56-58° C.and gatifloxacin T2RP hemihydrate (0.1 g) was added.

After seeding, the seeded solution was stirred for a seeding time of 2hours at the seeding temperature of 56-58° C., cooled to 5° C. overabout 8 hours, and maintained with stirring for 2 hours at thistemperature. The resulting slurry was filtered under vacuum and thecollected solid washed with acetonitrile (1.5 L) to obtain 865.3 g ofwet material.

The wet material was charged to a 10 L reactor and EtOH (6 L) was thencharged to the reactor. The slurry was stirred at 25° C. for 24 hours.The slurry was filtered under vacuum and washed with EtOH (1 L).

The wet material was loaded into a fluidized bed apparatus and treatedat 50° C. for 4 hours. After treatment in the fluidized bed drier, thematerial was found to be form T2RP by XRD analysis.

Example 27 Hydrated E1

A 140 liter reactor equipped with mechanical stirrer, condenser andthermometer, was charged with dimethyl sulfoxide (DMSO, 120 L). The DMSOwas heated to 55° C. and the reactor was charged with 2-methylpiperazine(8.6 kg). Gatifloxacin acid was charged, in four portions, every 2 hours(3×4=12 Kg). The reaction mixture was stirred at a rate of 110 rpm undernitrogen atmosphere. The temperature was maintained for 24 hours untilcompletion of the reaction. The reaction mixture was cooled to 48° C.and water (24 L) was added at this temperature. The mixture was cooledto 5° C. during 3.5 hours and maintained with stirring for 15 hours atthis temperature. The mixture was filtered (suction) and washed withacetonitrile (18 L) to obtain 15.9 Kg of gatifloxacin.

A 140 liter reactor equipped with mechanical stirrer, condenser andthermometer, was charged with the wet product from above (13.3 Kg,10-20% wetness) and 72 liter of water. The mixture was stirred at 25° C.for 1 hr. The slurry was filtered under vacuum and washed withacetonitrile (21 L) to obtain gatifloxacin wet material (17.5 Kg, about50% wetness).

A 140 liter reactor equipped with mechanical stirrer, condenser andthermometer, was charged with the wet material from the previous step(8.4 kg) and with acetonitrile (70.9 L). The mixture was then heated toreflux (80° C.) and stirred at a rate of 110 rpm. The heating wascontinued for 0.5 hours until a clear solution was obtained. The clearsolution was cooled to 60° C. and solvent was distilled-off under vacuum(100 mm Hg). After 3 hr, essentially all the solvent was removed.Acetonitrile (49 L) was charged and the mixture was heated to reflux(80° C.). The heating was continued for 0.5 hours until a clear solutionwas obtained.

The clear solution was filter through a-5, 1, 0.2-micron filter. Then500 ml of water was added and the clear solution was cooled to 62° C.and gatifloxacin (0.1 gr) was added. After addition, the stirring wasmaintained for 2 hours at 62° C., then the mixture was cooled during 3hours to 5° C. and maintained with the stirring for 1 hours at thistemperature. The resulting slurry was filtered under vacuum and washedwith acetonitrile (5 L) to obtain 5 kg of wet material.

The wet sample was form E1 by PXRD.

A portion of the wet material was loaded into a fluidized bed drier anddried at 25° C. for 6 hours. Gatifloxacin E1 dihydrate was obtained(water content by Karl-Fisher, 9.4%).

Example 28 E1 Dihydrate

1 Kg of gatifloxacin form E1 (6.5% water content by KF) was packed intoa Fluidized bed drier and treated at 25° C. for 6 hours. Gatifloxacinform E1 dihydrate was obtained (9.4% water content by Karl-Fisher).

Example 29 Interconversion of Forms by Thermal Treatment

Approximately 200 mg of several of the novel crystalline forms of thepresent invention, prepared as described in the foregoing examples, andseveral of the prior-art crystalline forms were subjected to variousthermal treatments. The treatments and the results are described inTable II below TABLE II XRD results of Gatifloxacin samples before andafter heating Starting form Heating conditions form Obtained A 50° C.,24 h, vacuum J or 60 C., 24 h B 50° C., 24 h, vacuum C F 50° C., 24 h,vacuum G G 120° C., 1 h Omega¹. I 60° C., 24 h, C Atmospheric pressure J120° C., 1 h omega sesquihydrate 120° C., 1 h T2RP + omega Hemihydrate120° C., 1 h T2RP T1RP 120° C., 1 h Hemihydrate¹Contains few additional XRD peaks

Example 30

200 mg of gatifloxacin form J were put in 80% relative humidity for 1week. The resulting sample was analyzed by XRD, TGA and KF. Theresulting sample was found to have the crystal structure of thesesquihydrate (LOD=7.8%, KF=6.6%).

Example 31

200 mg of gatifloxacin omega form were put in 80% relative humidity for1 week, and then analyzed by XRD and by TGA. The resulting sample wasfound to have sesquihydrate crystal structure (LOD=7.7%).

Example 32

200 mg of gatifloxacin form E1 were heated to 100° C. for 1 hour. TheXRD of the resulting sample was that of the omega form.

1-75. (canceled)
 76. A crystalline form of gatifloxacin characterized byx-ray reflections at about 7.1°, 7.3°, 10.8°, 15.7°, 16.4°, and18.1°±0.2° 2θ.
 77. The crystalline form of claim 76 containingacetonitrile, water, or mixtures thereof up to about 10% by weight. 78.A method of making the crystalline form of gatifloxacin of claim 77comprising the step of treating E1-ACN in a fluidized bed apparatus. 79.The method of claim 78 wherein the E1-ACN treated with moist gas at atemperature greater than about 30° C.
 80. A method of making thecrystalline form of gatifloxacin of claim 81 comprising the step ofexposing E1-ACN to 60% relative humidity.
 81. The crystalline form ofgatifloxacin of claim 77, designated E1 hydrate, comprising about 7.5%to 10% by weight water.
 82. A method of making the crystalline form ofgatifloxacin of claim 81 comprising the step of treating E1-ACN withmoist gas in a fluidized bed apparatus at a temperature greater thanabout 30° C.
 83. The method of making the crystalline form ofgatifloxacin of claim 82 wherein the gatifloxacin treated is firsttreated with moist gas at 20° to 30° C.
 84. A method of making thecrystalline form of gatifloxacin of claim 81 comprising the step ofexposing E1-ACN to 60% relative humidity. 85-87. (canceled)
 88. A methodof making the crystalline form of gatifloxacin a claim 80 comprising thesteps of: a) providing a solution of gatifloxacin in acetonitrile havingabout 5 wt % or less water at reflux, b) cooling the solution to aseeding temperature of about 57° to 70° C., c) seeding the solution atthe seeding temperature, d) cooling the seeded solution, and e)isolating the crystalline form of gatifloxacin.
 89. The method of claim88 wherein the seeded solution is maintained at the seeding temperaturefor a seeding time of at least about 30 minutes.
 90. The method of claim88 wherein the seeding temperature is about 60° C.
 91. The method ofclaim 88 wherein the seeded solution is cooled to about 5° C. or below.92. The method of claim 88 wherein the solution of gatifloxacin inacetonitrile has about 4.5 mt % or less water.
 93. A method of makingthe crystalline form of gatifloxacin of claim 80 comprising the step ofincubating gatifloxacin in acetonitrile vapors.
 94. A crystalline formof gatifloxacin, denominated E1-ACN, having up to about 10% acetonitrileand characterized by x-ray reflections at about 7.1°, 7.3°, 10.8°,15.7°, 16.4°, and 18.1°±0.2° 2θ, wherein the crystalline form is made bya process comprising the steps of: a) providing a solution ofgatifloxacin in acetonitrile having about 5 wt % or less water atreflux, b) cooling the solution to a seeding temperature of about 57° to70° C., c) seeding the solution at the seeding temperature, d) coolingthe seeded solution, and e) isolating the crystalline form ofgatifloxacin.
 95. The crystalline form of gatifloxacin of claim 94wherein the solution of gatifloxacin in acetonitrile has about 4.5 wt %or less water.
 96. The crystalline form of claim 94 wherein the seededsolution is maintained at the seeding temperature for a seeding time ofat least about 30 minutes.
 97. The crystalline form of claim 94 whereinthe seeding temperature is about 60° C.
 98. The crystalline form ofclaim 94 wherein the seeded solution is cooled to about 5° C. or below.99-107. (canceled)
 108. A method of making a hydrated gatifloxacin formE1 comprising the step of treating gatifloxacin form E1-ACN solvate witha moist gas at a temperature from ambient temperature to about 60° C.109. The method of claim 108 wherein the treating is at about 20° toabout 30° C. and the E1 dihydrate has a water content of about 7.5% toabout 10% on a weight basis.
 110. The method of claim 108 wherein themoist gas has a relative humidity between about 55% and about 75%. 111.The method of claim 108 wherein the treating is at about 50° C.
 112. Themethod of claim 108 wherein the treating is effected in a fluidized beddrying apparatus.
 113. A hydrated crystalline form of gatifloxacinhaving up to about 10% water or a mixture of water and acetonitrile andcharacterized by x-ray reflections at about 7.1, 7.3, 10.8, 15.7, 16.4,and 18.1×0.2 2ÿ, wherein the crystalline form is made by a processcomprising the step of treating gatifloxacin E1-ACN with moist gas at atemperature from ambient to about 60 C.
 114. The crystalline form ofgatifloxacin of claim 113 wherein the treating is at about 20 to about30 C and the crystalline form contains about 5% to about 7% water. 115.The crystalline form of claim 113 wherein the relative humidity of themoist gas is about 55% to about 75%.
 116. The crystalline form ofgatifloxacin of claim 113 wherein the treating is at about 50 C. 117.The crystalline form of claim 113 wherein the treating is in a fludizedbed apparatus. 118-131. (canceled)